Nearly half the global population suffers from oral inflammatory diseases, yet the mechanisms that drive the most destructive forms of periodontitis and peri-implantitis remain elusive. This study from the Human Periodontal Atlas consortium compared peri-implantitis with moderate- and high-grade periodontitis using an integrated approach combining microbial sequencing and single-cell transcriptomics on over 967,000 cells.

Laser capture microdissection with compartmental microbiome analysis revealed a surprising finding: peri-implantitis tissues harbor a reduced bacterial load and lower microbial diversity compared to periodontitis. The expansion of the Human Periodontal Atlas with new peri-implantitis data (36 samples; 121,395 cells) uncovered a critical vascular phenomenon — the rarefaction of CD34+ vascular endothelial cells alongside the enrichment of transcriptional programs linked to oxidative stress, hypoxia, and NAD⁺ metabolism.

A specific post-capillary venule subpopulation marked by TNFRSF6B⁺/ICAM1⁺ expression showed selective enrichment of CD38, an NAD⁺-consuming ectoenzyme. This was confirmed orthogonally through spatial transcriptomics and proteomics. Spatial neighborhood analysis demonstrated that CD38-high post-capillary venules expand and cluster in closer proximity in peri-implantitis, enhancing IL16-CD4 T cell signaling.

Critically, matched high-grade periodontitis biopsies confirmed spatially restricted CD38⁺ endothelial cells despite similar microbial burden, identifying endothelial vasculopathy — not bacterial load — as the common driver of rapidly advancing oral inflammation. This opens a potential therapeutic axis targeting CD38⁺ endothelial dysfunction, shifting the paradigm from microbial-centric to vascular-centric understanding of aggressive periodontal destruction.